Heart disease and its manifestations, including coronary artery disease, myocardial infarction, congestive heart failure and cardiac hypertrophy, clearly present a major health risk in the United States today. The cost to diagnose, treat and support patients suffering from these diseases is well into the billions of dollars. One particularly severe manifestation of heart disease is myocardial infarction.
Myocardial infarction, commonly known as a heart attack, is caused by a sudden and sustained lack of blood flow to the heart tissue, which is usually the result of a narrowing or occlusion of a coronary artery. Without adequate blood supply, the tissue becomes ischemic, leading to the death of cardiomyocytes (e.g. heart muscle cells) and vascular structures. The necrotic tissue resulting from the death of the cardiomyocytes is generally replaced by scar tissue, which is not contractile, fails to contribute to cardiac function, and often plays a detrimental role in heart function by expanding during cardiac contraction, or by increasing the size and effective radius of the ventricle, for example, becoming hypertrophic.
Recently, key roles of microRNAs in heart failure have been described, pointing to a new mode of regulation of cardiac disease. MicroRNAs (miRNAs) are small, non-protein coding RNAs of about 18 to about 25 nucleotides in length that are derived from individual miRNA genes, from introns of protein coding genes, or from poly-cistronic transcripts that often encode multiple, closely related miRNAs. See review by Carrington et al. (Science, Vol. 301(5631):336-338, 2003). MiRNAs act as repressors of target mRNAs by promoting their degradation, when their sequences are perfectly complementary, or by inhibiting translation, when their sequences contain mismatches.
MiRNAs are transcribed by RNA polymerase II (pol II) or RNA polymerase III (pol III; see Qi et al. (2006) Cellular & Molecular Immunology, Vol. 3:411-419) and arise from initial transcripts, termed primary miRNA transcripts (pri-miRNAs), that are generally several thousand bases long. Pri-miRNAs are processed in the nucleus by the RNase Drosha into about 70- to about 100-nucleotide hairpin-shaped precursors (pre-miRNAs). Following transport to the cytoplasm, the hairpin pre-miRNA is further processed by Dicer to produce a double-stranded miRNA. The mature miRNA strand is then incorporated into the RNA-induced silencing complex (RISC), where it associates with its target mRNAs by base-pair complementarity. In the relatively rare cases in which a miRNA base pairs perfectly with an mRNA target, it promotes mRNA degradation. More commonly, miRNAs form imperfect heteroduplexes with target mRNAs, affecting either mRNA stability or inhibiting mRNA translation.
Recently, signature expression patterns of miRNAs associated with pathological cardiac hypertrophy, heart failure and myocardial infarction in humans and mouse models of heart disease have been identified (van Rooij et al (2006) Proc. Natl. Acad. Sci., Vol. 103(48):18255-60; van Rooij et al., (2007) Science, Vol. 316: 575-579). Gain- and loss-of-function studies in mice have revealed profound and unexpected functions for these miRNAs in numerous facets of cardiac biology, including the control of myocyte growth, contractility, energy metabolism, fibrosis, and angiogenesis, providing glimpses of new regulatory mechanisms and potential therapeutic targets for heart disease. Remarkably, knockout mice lacking disease-inducing miRNAs are normal, but display aberrant responses to cardiac stress, suggesting the dedication of these miRNAs to disease-related processes rather than tissue homeostasis, and pointing to their potential as therapeutic targets. Thus, miRNAs represent potential novel therapeutic targets for the development of treatments for a variety of diseases, including cardiovascular diseases, obesity, diabetes, and other metabolic disorders.
Aging is associated with impaired cardiac function (1), however, though miRNAs have recently emerged as key regulators of cardiovascular function (3, 4), miRNAs have thus far not been implicated in aging of the heart. Thus, identification and characterization of miRNAs dysregulated in the heart during aging, as well as the targets of the miRNAs, is important for the development of novel therapeutic approaches for the treatment of age-related cardiomyopathies, and cardiovascular diseases, such as myocardial infarction.